Tolerance to sympathomimetic bronchodilators in guinea-pig isolated lungs following chronic administration in vivo.

1 Pretreatment of the guinea-pig subcataneously three times daily with either 5 mug/kg isoprenaline or adrenaline reduced the response of the isolated perfused histamine-constricted lung when challenged with either the same or a different sympathomimetic bronchodilator. The longer the animals were pretreated and the higher the dose of bronchodilator the greater was the degree of tolerance developed. 2 Tolerance was developed to aminophline in the same preparation when the guinea-pig had been pretreated with aminophyline or isoprenaline. Cross-tolerance also developed adrenaline when the guinea-pig had been pretreated with aminophyline. 3 Tolerance was still persistent in guinea-pigs one and two weeks after pretreatment three times daily with either isoprenaline of adrenaline (5 mu/kg s.c.) for seven days in the same preparation. Only after three weeks was the tolerance diminished. 4 These results suggest that asthmatic patients who use bronchodilators excessively may become refractory to the bronchodilator effect of these drugs. They also support the hypothesis that induced cross-resistance to endogenous sympathetic stimulation could lead to a deterioration of the asthmatic state in patients using the sympathomimetic bronchodilators and that this may explain the increase in asthma mortality rate. 5 A mechanism of tolerance to sympathomimetic bronchodilators is postulated.